APOPTOTIC TUMOR-CELL DEATH INDUCED BY ESTRAMUSTINE IN PATIENTS WITH MALIGNANT GLIOMA

Estramustine phosphate (EMP), a cytotoxic drug used in the treatment o f prostatic carcinoma, is metabolized and exerts specific cytotoxic ef fects in malignant glioma in vitro and in vive, In the present study, we have evaluated the cytotoxic effect of EMP in the clinical situatio n with regard to appearance of DNA damage and its correlation to the u ptake of estramustine (EaM) in human malignant astrocytoma tissue, Ten patients were given 280 mg of EMP p.o. 12 h before surgery, Specimens from brain tumor tissue were collected during surgery and used for de tection ag fragmented DNA, a hallmark of apoptosis, with in situ end l abeling (ISEL) and agarose gel techniques, The main metabolite of EMP in glioma tissue, EaM, was analyzed with gas chromatography. It was de monstrated that EMP induced clusters of ISEL-positive tumor cells and fragmentation of DNA on agarose gels in patients treated with EMP. In the same patients, a significant uptake of EaM in tumor tissue was dem onstrated, In control patients, who were not treated with EMP, and in two EMP-treated patients with no uptake of EaM, no signs of fragmented DNA and only a few scattered ISEL-positive cells were seen in the tum or tissue, Signs of apoptosis were also seen in two different experime ntal models, i.e., in vitro cell cultures of rat glioma cells and an i n vive rat glioma model, It is suggested that EaM can induce apoptosis by a direct effect oil a subpopulation of glioma cells in human brain tumors in the clinical situation.